Irbesartan, 2-n-butyl-4-spirocyclopentane-1-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]- 2-imidazolin-5-one, is a potent, long-acting angiotensin II receptor antagonist which is particularly useful in the treatment of cardiovascular ailments such as hypertension and heart failure. Irbesartan has the following structure: ##STR1## and is described in Bernhart et al., U.S. Pat. No. 5,270,317, incorporated herein by reference. Preferred pharmaceutical compositions of this drug contain, as active ingredient(s), irbesartan alone or in combination with a diuretic such as hydrochlorothiazide.
Irbesartan may be administered in dosages containing a substantial quantity of the active agent (e.g., 75-300 mg). Certain physical properties of the drug present a challenge in developing formulations suitable for preparing a tablet having both a substantial quantity of active agent and a small enough tablet mass to allow ease of swallowing.
Irbesartan is, for example, a fluffy material, with relatively low bulk and tap densities. These properties make it difficult to formulate a large amount of the drug into a small tablet with uniformity of weight, hardness, and other desirable tablet properties. In addition, irbesartan has certain undesirable flow characteristics, for example, is sticky and can adhere to surfaces such as tablet punch faces and dies, causing problems in tableting, especially on a high speed tablet press. The low aqueous solubility of irbesartan also presents a challenge, since, to keep the tablet mass small, only limited amounts of excipients may be added to facilitate wetting, disintegration, and ultimately, rapid and complete drug release. The addition of a diuretic such as hydrochlorothiazide, which is also a fluffy material exhibiting poor flow and low aqueous solubility, can further contribute to tableting problems.
Thus, there is a need in the art for pharmaceutical compositions containing irbesartan, alone or in combination with a diuretic, which have good properties for tablet formation, and yet which contain a low mass of excipients so that small, easily swallowed tablets with a high content of active agent may be prepared.